Audrey M. Bernstein

Research

Corneal Wound Healing

Our lab is studying the mechanisms that regulate wound healing in the cornea. The cornea refracts light as it enters the eye so that a properly focused image reaches the retina. Maintaining corneal transparency is critical for clear, unobstructed vision. When a cornea is wounded by surgery or injury, the wound heals unpredictably, either regeneratively (without scarring) or fibrotically (with scarring). Corneal scars may be opaque, and cause severe visual defects. Our goal is to understand the mechanisms that promote regenerative wound healing over fibrotic healing.

Corneal wound healing begins when cells (fibroblasts) migrate into the wound site. Upon reaching the wound, fibroblasts begin producing repair matrix and differentiate into contractile cells (myofibroblasts) that adhere to the surrounding matrix and pull the matrix fibers together, closing the wound. Proper spacing and alignment of fibers is essential for an optically clear tissue. In a regeneratively healed wound, myofibroblasts disappear by apoptosis, whereas the persistence of myofibroblasts results in the overproduction of extracellular matrix and excessive contraction, leading to scarring. Regulation of both fibroblast migration and myofibroblast differentiation are critical for promoting regenerative repair.

To better understand the molecular basis for cell migration and cell differentiation, we have focused on the role of the urokinase (uPA) pathway during wound healing. uPA is an extracellular serine protease that stimulates both a protease cascade at the cell-matrix interface and an intracellular signaling cascade resulting in cytoskeletal reorganization and cell migration. We have found dramatic differences in the uPA pathway between fibroblasts and myofibroblasts leading us to conclude that this pathway is important for both fibroblast migration and regulation of myofibroblast differentiation.

Future work will examine the importance of the extracellular matrix composition after wounding. The matrix appears to change throughout wound healing and understanding the specific, time-dependent changes is critical to fully understand the interactions of cells and matrix and their specific roles in regulating cell migration and differentiation. Furthermore, this is a particularly exciting time in this field as we recognized that multiple pathways are involved in this very important repair process. Consequently, we are beginning to study uPA pathway interactions with growth factors and their downstream targets in order to develop a comprehensive picture of how corneal healing may be controlled to provide a perfect optical surface to maintain clear vision.

Research Topics

• Cell adhesion and extracellular matrix
• Cell migration
• Cell differentiation
• Proteases